برجاء الإنتظار ...

Search Results



نشرة الممارس الصحي نشرة معلومات المريض بالعربية نشرة معلومات المريض بالانجليزية صور الدواء بيانات الدواء
  SFDA PIL (Patient Information Leaflet (PIL) are under review by Saudi Food and Drug Authority)

Methotrexate Injection is an anti-metabolite medicine (medicine which affects how the body’s cells grow) and immunosuppressant (medicine which reduces the activity of the immune system).

 

Methotrexate is used in large doses (on its own or in combination with other medicines) to treat certain types of cancer such as breast cancer. In smaller doses it can be used to treat severe psoriasis (a skin disease with thickened patches of inflamed red skin, often covered by silvery scales), when it has not responded to other treatments.


You will not be given Methotrexate Injection if you

·            are allergic (hypersensitive) to Methotrexate or any of the other ingredients of Methotrexate Injection

·            have significant kidney or liver problems

·            have been told you have (or think you have) a blood disorder such as low levels of white blood cells, red blood cells (anaemia) or platelets

·            have any infection

·            your immune system is not working as well as it should

·            are breast-feeding and additionally, for non-oncologic indications (for non-cancer treatment) if you are pregnant (see section ‘Pregnancy, breast-feeding and fertility’)

 

Tell your doctor if any of the above applies to you before this medicine is used.

 

Warnings and precautions

 

Acute bleeding from the lungs in patients with underlying rheumatologic disease has been reported with methotrexate. If you experience symptoms of spitting or coughing up blood you should contact your doctor immediately.

 

If you, your partner or your caregiver notice new onset or worsening of neurological symptoms including general muscle weakness, disturbance of vision, changes in thinking, memory and orientation leading to confusion and personality changes contact your doctor immediately because these may be symptoms of a very rare, serious brain infection called progressive multifocal leukoencephalopathy (PML).

 

Methotrexate temporarily affects sperm and egg production. Methotrexate can cause miscarriage and severe birth defects. You should avoid having a baby if you are being given methotrexate at the time and for at least 6 months after the end of your treatment with methotrexate if you are a woman. If you are a man you should avoid fathering a child if you are being given methotrexate at the time and for at least 3 months after the end of your treatment. See also section ‘Pregnancy, breast-feeding and fertility’.

 

Methotrexate may make your skin more sensitive to sunlight. Avoid too much sun and do not use a sun-lamp or sun-bed. Before you go out in the sun, use a sun-protection product with a high protection factor. Always wear a hat and clothes which cover your arms and legs.

 

Take special care with Methotrexate Injection if you

·            have a stomach ulcer or ulcerative colitis (inflammation and ulceration of the gut)

·            have an infection

·            have mild kidney problems

·            have a medical condition which causes a build-up of fluid in the lining of your lungs or in your abdomen (the fluid will need to be drained before methotrexate treatment is started)

·            are to have radiotherapy (risk of tissue and bone damage may be increased)

·            are to have any vaccinations

 

Tell your doctor if any of the above applies to you before this medicine is used.

 

Special care will also be taken in children, the elderly and in those who are in poor physical condition.

 

Recommended follow-up examinations and precautions

Even if methotrexate is used in low doses, serious side effects can occur. In order to detect them in time, your doctor must perform monitoring examinations and laboratory tests.

 

Prior to the start of therapy:

Before you start treatment, your blood will be checked to see if you have enough blood cells. Your blood will also be tested to check your liver function and to find out if you have hepatitis. Furthermore, serum albumin (a protein in the blood), hepatitis (liver infection) status and kidney function will be checked. The doctor may also decide to run other liver tests, some of these may be images of your liver and others may need a small sample of tissue taken from the liver in order to examine it more closely. Your doctor may also check to see if you have tuberculosis, and they may X-ray your chest or perform a lung function test.

 

During the treatment:

Your doctor may perform the following examinations:

-      examination of the oral cavity and the pharynx for changes in the mucous membrane such as inflammation or ulceration

-      blood tests/ blood count with number of blood cells and measurement of serum methotrexate levels

-      blood test to monitor liver function

-      imaging tests to monitor liver condition

-      small sample of tissue taken from the liver in order to examine it more closely

-      blood test to monitor kidney function

-      respiratory tract monitoring and, if necessary, lung function test

 

It is very important that you appear for these scheduled examinations.

 

If the results of any of these tests are conspicuous, your doctor will adjust your treatment accordingly.

 

Elderly patients

Elderly patients under treatment with methotrexate should be monitored closely by a physician so that possible side effects can be detected as early as possible. Age-related impairment of liver and kidney function as well as low body reserves of the vitamin folic acid in old age require a relatively low dosage of methotrexate.

 

Taking/using other medicines

 

Special care is needed if you are taking/using other medicines as some could interact with methotrexate, for example:

·            non-steroidal anti-inflammatory medicines e.g. ibuprofen (medicines taken for pain relief)

·            aspirin or similar medicines (known as salicylates)

·            omeprazole, esomeprazole and pantoprazole (medicines used to reduce the production of stomach acid)

·            diuretics (water tablets)

·            medicines taken for diabetes (including insulin and tablets)

·            antibiotics such as penicillins, sulphonamides, co-trimoxazole, trimethoprim, tetracycline, chloramphenicol and para-aminobenzoic acid

·            phenytoin (medicine often used to treat epilepsy)

·            vitamin supplements containing folic acid

·            probenecid (medicine used to treat gout)

·            nitrous oxide (used for general anaesthesia and pain relief). Nitrous oxide increases the effect of Methotrexate and can lead to an increase in some side effects (such as reduced number of blood cells and platelets and inflammation of mouth). Following injection into the spine it can have an effect on your nervous system

·            retinoids, such as acitretin (a medicine used to treat psoriasis) or isotretinoin (used to treat severe acne)

·            other drugs that may cause damage to your kidneys

·            other drugs that may cause damage to your liver

·            live virus vaccines

·            mercaptopurine (medicine used in the treatment of blood cell cancer)

·            theophylline (medicine used in the treatment of asthma)

 

Please tell your doctor if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

 

Using Methotrexate Injection and drinking alcohol

Do not drink alcohol whilst being treated with Methotrexate as alcohol increases the risk of liver damage.

 

Pregnancy, breast-feeding and fertility

Tell your doctor if you are pregnant, trying to become pregnant or breast-feeding before this medicine is used.

 

Pregnancy

Do not use Methotrexate during pregnancy except if your doctor has prescribed it for oncology treatment. Methotrexate can cause birth defects, harm the unborn child or cause miscarriage. It is associated with malformations of the skull, face, heart and blood vessels, brain, and limbs. It is therefore very important that methotrexate is not given to pregnant women or to women who are planning to become pregnant unless used for oncology treatment.

 

For non-oncological indications, in women of child-bearing age the possibility of a pregnancy must be ruled out, e.g. by pregnancy tests, before treatment is started.

 

Do not use Methotrexate if you are trying to become pregnant. You must avoid becoming pregnant during treatment with methotrexate and for at least 6 months after the end of treatment. Therefore, you must ensure that you are taking effective contraception for the whole of this period (see also section "Warnings and precautions").

 

If you become pregnant during treatment or suspect you might be pregnant, speak to your doctor as soon as possible. If you do become pregnant during treatment, you should be offered advice regarding the risk of harmful effects on the child through treatment.

If you want to become pregnant, you should speak with your doctor, who may refer you for specialist advice before the planned start of treatment.

 

Mothers should not breast-feed whilst treatment with methotrexate is ongoing.

 

Male fertility

The available evidence does not indicate an increased risk of malformations or miscarriage if the father takes methotrexate less than 30 mg/week. However, a risk cannot be completely excluded and there is no information regarding higher methotrexate doses. Methotrexate can have a genotoxic effect. This means that the medicine can cause genetic mutations. Methotrexate can affect the production of sperm, which is associated with the possibility of birth defects.

 

You should avoid fathering a child or donating semen during treatment with methotrexate and for at least 3 months after the end of treatment. As treatment with methotrexate at higher doses commonly used in cancer treatment can cause infertility and genetic mutations, it may be advisable for male patients treated with methotrexate doses higher than 30 mg/week to consider sperm preservation before the beginning of treatment (see also section "Warnings and precautions").

 

Ask your doctor or pharmacist for advice before taking any medicine.

 

Driving and using machines

Do not drive or use machines if you experience any side effect (e.g. dizziness, drowsiness or blurred vision) which may lessen your ability to do so.

 

Information on sodium content in Methotrexate Injection

Methotrexate 50 mg/2 ml contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium-free’.

 

Methotrexate 500 mg/20 ml contains 41.1 mg sodium (main component of cooking/table salt) per vial. This is equivalent to 2.06% of the recommended maximum daily dietary intake of sodium for an adult.


This medicine may be given by injection into a vein (intravenous injection), into muscle (intramuscular injection), into an artery (intraarterial injection) or into the spine (intrathecal injection)*. It may also be given by infusion (drip) into a vein. It may be diluted before it is given.

 

* Of the presentations available (see section 6) only the 50 mg/2 ml is suitable for intrathecal injection.

 

Recommended dose

Your doctor will work out the correct dose of Methotrexate Injection for you and how often it must be given.

 

The dose of medicine given to you will depend on the disease being treated, your medical condition, your age, your size and how well your kidneys are working.

 

Dose in severe psoriasis:

Take Methotrexate only once a week.

 

Important warning about the dose of Methotrexate Injection:

 

Use Methotrexate Injection only once a week for the treatment of psoriasis. Using too much of Methotrexate Injection may be fatal. Please read section 3 of this leaflet very carefully. If you have any questions, please talk to your doctor or pharmacist before you take this medicine.

 

 

If you are given too much or too little Methotrexate Injection

This medicine will be given to you in a hospital, under the supervision of a doctor. It is unlikely that you will be given too much or too little, however, tell your doctor or nurse if you have any concerns.


Methotrexate is a very toxic medicine and patients have died, or become very ill, whilst being treated with it. During treatment you should watch for any side effects and report them to the doctor.

 

If any of the following happen, tell your doctor immediately:

·            severe allergic reaction - you may experience a sudden itchy rash (hives), swelling of the hands, feet, ankles, face, lips, mouth or throat (which may cause difficulty in swallowing or breathing), and you may feel you are going to faint

·            inflammation of the lung with breathlessness – you may develop a persistent cough, experience pain or difficulty breathing, or become breathless. This may be associated with changes in a particular type of white cell in your blood.

·            spitting or coughing blood*

·            symptoms of an infection e.g. fever, chills, achiness, sore throat

·            unexpected bleeding e.g. bleeding gums, blood in the urine or in vomit, or the appearance of unexpected bruises or broken blood vessels (broken veins)

·            black tarry stools

·            a sore mouth, particularly if you have a number of ulcers or blisters inside of the mouth or on the tongue

·            skin rashes or blistering to the surfaces of the eyes, nose, vagina or anus (back passage)

·            diarrhoea

·            stroke/ weakness on one side of the body

·            weakness in the legs that spreads to the upper limbs and the face, which may result in paralysis

·            abdominal pain, fatty stools, vomiting

·            chest pain (which may be due to heart or lung problems)

 

*(has been reported for methotrexate used in patients with underlying rheumatologic disease)

 

These are serious side effects. You may need urgent medical attention.

 

If any of the following happen, tell your doctor as soon as possible:

·            low blood pressure (you may feel faint)

·            fits

·            blurred vision

·            dizziness

·            difficulty/inability to talk

·            muscle weakness

·            you may feel the need to drink more than usual (diabetes)

·            abnormally easily broken bones (osteoporosis)

·            pain or redness of the blood vessels (vasculitis)

·            itching or the appearance of lightened patches on the skin, bruises, boils

·            skin that is more sensitive to sunlight than normal. You may get a skin rash, redness, swelling or severe sunburn

·            acne

·            yellowing of the skin and whites of the eyes (jaundice)

·            pain in the stomach, loins or abdomen

·            you may need to pass urine more often than normal, which may be painful (cystitis)

·            headaches

·            drowsiness

·            generally feeling tired or unwell

·            reduced appetite, feeling or being sick

·            irregular periods in women (periods may stop completely)

·            hair loss

·            effects on learning and memory

·            ringing in the ears

·            joint and muscle pain

·            blood clot which causes pain, swelling or redness (cerebral, deep vein, retinal vein or arterial vein)

·            mood alterations

·            inflammation of the lungs, which causes breathlessness, cough and raised temperature, pneumonia

·            shingles (Herpes Zoster)

·            bleeding from the lungs (frequency not known)*

·            lymphoproliferative disorders (excessive growth of white blood cells) (frequency very rare)

·            bone damage in the jaw (secondary to excessive growth of white blood cells) (frequency not known)

·            redness and shedding of skin (frequency not known)

·            sensation of numbness or tingling, having less sensitivity to stimulation than normal (frequency very rare)

·            swelling (frequency not known)

·            injection site reaction (frequency not known)**

·            dark red or black patches of skin around the injection site, often accompanied with pain (Injection site necrosis) (frequency not known)**

 

*(has been reported for methotrexate used patients with underlying rheumatologic disease).

**(parenteral only).

 

Some different side effects may occur following injection into the spine. These are

·            headache

·            back or shoulder pain

·            difficulty with bending your head down

·            fever

·            temporary paralysis or weakness

·            problems with a particular part of your brain, leading to shaking, abnormal balance or staggering.

·            Irritability and confusion

·            Stiffness

·            Fits

·            Confusion and loss of memory

·            Sleepiness

·            Coma

·            Death

 

Methotrexate may lead to problems with your blood, liver and kidneys. Your doctor will take blood samples to check for these problems and may ask you to have an operation to have a small sample of your liver removed.

 

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor.

 

Effects on fertility

Treatment with methotrexate may reduce fertility in men and women. Fertility is thought to go back to normal after methotrexate treatment is stopped. Tell your doctor if you have concerns.

 

Post-marketing adverse drug reaction: Non-melanoma skin cancer as a very rare adverse drug event.

 

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects, you can help provide more information on the safety of this medicine.

 

By reporting side effects

 

·       Saudi Arabia

 

National Pharmacovigilance Centre (NPC)

  • Call center: 19999
  • E-mail: npc.drug@sfda.gov.sa
  • Website: https://ade.sfda.gov.sa/

 

·       Other GCC states

 

-        Please Contact the relevant competent authority.


Keep out of the reach and sight of children

 

Expiry

This medicine must not be used after the expiry date which is stated on the vial label and carton after 'EXP'. Where only a month and year is stated, the expiry date refers to the last day of that month.

 

Storage

The vials should be kept in the outer carton, in order to protect from light, and stored below 25°C. The vials should not be frozen.

Unused portions of opened vials must not be stored for later use.

Prepared infusions should be used immediately, however, if this is not possible they can, in certain circumstances, be stored for up to 30 days in a refrigerator provided they have been prepared in a way to exclude microbial contamination.


The active substance is methotrexate. Each millilitre (ml) of solution contains 25 milligrams (mg) of methotrexate.

 

The other ingredients are sodium chloride, sodium hydroxide (see section 2 “Methotrexate Injection contains Sodium”) and Water for Injections.


Methotrexate Injection is a clear, yellow solution for injection which comes in glass containers called vials. It may be supplied in packs containing: • 5 x 50 mg/2 ml vials • 1 x 500 mg/20 ml vial

Marketing Authorisation Holder

Hospira UK Limited, Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, United Kingdom.

 

Manufacturer

Hospira Australia Pty Ltd, 1-5, 7-23 and 25-39 Lexia Place,

MULGRAVE VIC 3170, Australia


October 2023
  نشرة الدواء تحت مراجعة الهيئة العامة للغذاء والدواء (اقرأ هذه النشرة بعناية قبل البدء في استخدام هذا المنتج لأنه يحتوي على معلومات مهمة لك)

حقن ميثوتريكسات هي دواء مضاد لنواتج الأيض (دواء يؤثر على كيفية نمو خلايا الجسم) وكابت للمناعة (دواء يقلل من نشاط الجهاز المناعي).

 

يستخدم ميثوتريكسات بجرعات كبيرة (بمفرده أو بالتزامن مع أدوية أخرى) لعلاج أنواع معينة من السرطان مثل سرطان الثدي. يمكن استخدام ميثوتريكسات بجرعات أصغر لعلاج الصدفية الشديدة (مرض جلدي يتميز بوجود رقع سميكة من الجلد الأحمر الملتهب غالبًا ما تغطيها قشور فضية)، إذا لم تستجب للعلاجات الأخرى.

 

موانع استعمال ميثوتريكسات

·            إذا كنت تعاني من حساسية (مفرط الحساسية) تجاه ميثوتريكسات أو أي من مكونات حقن ميثوتريكسات الأخرى

·            إذا كنت تعاني من مشكلات خطيرة بالكلى أو الكبد

·            إذا كان قد تم إخبارك بأنك تعاني (أو تعتقد بأنك تعاني) من اضطراب في الدم مثل انخفاض مستويات خلايا الدم البيضاء أو خلايا الدم الحمراء (فقر الدم) أو الصفيحات الدموية

·            إذا كنت تعاني من أي عدوى

·            إذا كان جهازك المناعي لا يعمل كما ينبغي

·            إذا كنتِ ترضعين، وأيضًا، في حالة دواعي الاستعمال غير المتعلقة بالأورام (للعلاج غير المتعلق بالسرطان) إذا كنتِ حاملًا (انظر قسم "الحمل والرضاعة")

 

أخبر طبيبك إذا كانت أي من الحالات المذكورة أعلاه تنطبق عليك قبل أن يتم استخدام هذا الدواء.

 

الاحتياطات عند استعمال ميثوتريكسات

 

تم الإبلاغ عن حالات نزيف حاد من الرئتين في المرضى الذين يعانون من أمراض الروماتيزم الكامنة مع العلاج بميثوتريكسات. إذا عانيت من أعراض بصق أو سعال الدم، ينبغي لك التواصل مع طبيبك على الفور.

 

إذا لاحظت أنت أو شريكتك أو القائم على رعايتك ظهور أعراض عصبية جديدة أو تفاقمها، بما في ذلك ضعف العضلات العام، واضطراب الرؤية، وتغيرات في التفكير والذاكرة والتوجه تؤدي إلى الارتباك وتغيرات في الشخصية، فاتصل بطبيبك فورًا لأنها قد تكون أعراض عدوى دماغية خطيرة ونادرة جدًا تسمى اعتلال بيضاء الدماغ متعدد البؤر التقدمي (PML).

 

يؤثر ميثوتريكسات مؤقتًا على إنتاج الحيوانات المنوية والبويضات. يمكن أن يتسبب ميثوتريكسات في الإجهاض وحدوث تشوهات ولادية شديدة. إذا كان يتم إعطاؤكِ ميثوتريكسات، ينبغي أن تتجنبي إنجاب طفل في وقت علاجكِ بميثوتريكسات ولمدة ٦ أشهر على الأقل بعد نهاية العلاج إذا كنتِ سيدة. وأما إذا كنت رجلًا، ينبغي أن تتجنب إنجاب طفل في حالة إعطائك ميثوتريكسات في هذا الوقت ولمدة ۳ أشهر على الأقل بعد انتهاء علاجك. انظر أيضًا قسم "الحمل والرضاعة".

 

قد يزيد ميثوتريكسات من حساسية جلدك تجاه ضوء الشمس. تجنب التعرض لأشعة الشمس لفترة طويلة ولا تستخدم المصابيح الشمسية أو حمامات الشمس الاصطناعيّة. قبل التعرض للشمس، استخدم منتجًا واقيًا من الشمس بعامل حماية عالٍ. وارتدِ دائمًا قبعة وملابس تغطي ذراعيك وساقيك.

 

توخ الحذر بشكل خاص مع حقن ميثوتريكسات إذا

·            كنت تعاني من قرحة في المعدة أو التهاب القولون التقرحي (التهاب وتقرح يصيب الأمعاء)

·            كنت تعاني من عدوى ما

·            كنت تعاني من مشكلات خفيفة في الكلى

·            كنت تعاني من حالة طبية تسبب تراكم السوائل في بطانة رئتيك أو في بطنك (سوف يلزم تصريف السائل قبل بدء العلاج بميثوتريكسات)

·            كان يفترض بك تلقي علاج إشعاعي (يمكن أن يزداد خطر تلف الأنسجة والعظم)

·            كان يفترض بك تلقي أي لقاحات

 

أخبر طبيبك إذا كانت أي من الحالات المذكورة أعلاه تنطبق عليك قبل أن يتم استخدام هذا الدواء.

 

سيتم توخي الحذر بشكل خاص أيضًا في الأطفال والمسنين وفي الأشخاص ذوي الحالة البدنية السيئة.

 

فحوصات المتابعة والاحتياطات الموصى بها

حتى إذا استُخدم ميثوتريكسات بجرعات منخفضة، فقد تحدث إصابة بآثار جانبية خطيرة. ومن أجل اكتشافها في الوقت المناسب، يجب أن يُجري طبيبك فحوصات واختبارات معملية لمراقبة الحالة.

 

قبل بدء العلاج:

قبل أن تبدأ العلاج، سيُفحص دمك لمعرفة ما إذا كان لديك خلايا دم كافية. وأيضًا، ستُجرى اختبارات على دمك لفحص وظائف الكبد ومعرفة ما إذا كنت مصابًا بالتهاب الكبد أم لا. علاوةً على ذلك، سيفحص مستوى الألبومين (بروتين في الدم) في مصل الدم وحالة التهاب الكبد (عدوى تصيب الكبد) ووظائف الكلى. وقد يقرر الطبيب كذلك إجراء اختبارات أخرى على الكبد، قد يكون بعضها عبارة عن فحوصات لتصوير كبدك بالأشعة والبعض الآخر قد يحتاج إلى أخذ عينة صغيرة من أنسجة الكبد لفحصها عن كثب. وقد يفحصك طبيبك أيضًا لمعرفة ما إذا كنت مصابًا بالسل، وقد يُجري أشعة سينية على صدرك أو اختبارًا لوظائف الرئة.

 

أثناء العلاج:

قد يُجري طبيبك الفحوصات التالية:

-        فحص تجويف الفم والبلعوم تحسبًا لوجود تغيرات في الغشاء المخاطي مثل الالتهاب أو التقرح

-        فحوصات الدم/تعداد الدم التي توضح عدد خلايا الدم وقياسات مستويات ميثوتريكسات في الدم

-        فحوصات الدم المُجراة لمراقبة وظائف الكبد

-        اختبارات التصوير بالأشعة لمراقبة حالة الكبد

-        أخذ عينة صغيرة من أنسجة الكبد لفحصها عن كثب

-        فحص دم لمراقبة وظائف الكلى

-        مراقبة القناة التنفسية، وإذا لزم الأمر، اختبار لوظائف الرئة

 

مهم جدًا أن تلتزم بالخضوع لهذه الفحوصات المرتقبة.

 

إذا كانت نتائج أي من هذه الاختبارات جديرة بالانتباه، فسوف يعدل طبيبك علاجك وفقًا لذلك.

 

المرضى المسنون

ينبغي أن يراقب طبيب المرضى المسنين الخاضعين للعلاج بميثوتريكسات عن كثب حتى يمكن اكتشاف الآثار الجانبية واردة الحدوث في مرحلة مبكرة قدر الإمكان. ذلك أن حالات الخلل المرتبطة بالعمر التي تؤثر في وظائف الكبد والكلى بالإضافة إلى انخفاض مخزون الجسم من فيتامين حمض الفوليك في سن الشيخوخة تتطلب إعطاء جرعة منخفضة نسبيًا من ميثوتريكسات.

 

التداخلات الدوائية مع أخذ هذا المستحضر مع أي أدوية أخرى أو أعشاب أو مكملات غذائية

 

يلزم توخي الحذر بشكل خاص إذا كنت تتناول/تستخدم أدوية أخرى حيث إن بعضها يمكن أن يتفاعل مع ميثوتريكسات، على سبيل المثال:

·            مضادات الالتهاب غير الستيرويدية مثل إيبوبروفين (أدوية يتم تناولها لتسكين الألم)

·            الأسبرين أو الأدوية المشابهة له (تعرف بالساليسيلات)

·            أوميبرازول، وإيسوميبرازول، وبانتوبرازول (أدوية تستخدم لتقليل إفراز حمض المعدة)

·            مدرات البول (أقراص الماء)

·            الأدوية التي يتم تناولها لعلاج السكري (بما في ذلك الإنسولين والأقراص)

·            المضادات الحيوية مثل البنسلينات، والسلفوناميدات، وكو-تريموكسازول، وتريميثوبريم، وتتراسيكلين، وكلورامفينيكول، وحمض البارا-أمينوبنزويك

·            فنيتوين (دواء يستخدم غالبًا لعلاج الصرع)

·            المكملات الفيتامينية التي تحتوي على حمض الفوليك

·            بروبينيسيد (دواء يستخدم لعلاج النقرس)

·            أكسيد النيتروز (يستخدم للتخدير العام وتسكين الألم). يزيد أكسيد النيتروز من آثار ميثوتريكسات ويمكن أن يؤدي إلى زيادة في بعض الآثار الجانبية (مثل انخفاض عدد خلايا الدم والصفيحات الدموية والتهاب الفم). بعد الحقن داخل الحبل الشوكي يمكن أن يؤثر على جهازك العصبي

·            الرتينويدات، مثل أسيتريتين (دواء يستخدم لعلاج الصدفية) أو أيزوتريتينوين (يستخدم لعلاج حب الشباب الشديد)

·            العقاقير الأخرى التي يمكن أن تسبب تلفًا لكليتيك

·            العقاقير الأخرى التي يمكن أن تسبب تلفًا لكبدك

·            لقاحات الفيروسات الحية

·            ميركابتوبيورين (دواء يستخدم في علاج سرطان خلايا الدم)

·            ثيوفيلين (دواء يستخدم في علاج الربو)

 

يرجى إبلاغ طبيبك إذا كنت قد تلقيت مؤخرًا، أو تتلقى حاليًا، أي أدوية أخرى بما في ذلك الأدوية التي يمكن الحصول عليها بدون وصفة طبية.

 

تناول حقن ميثوتريكسات مع الطعام والشراب

لا تشرب الكحوليات أثناء الخضوع للعلاج بميثوتريكسات حيث إن الكحول يزيد من خطر تلف الكبد.

 

الحمل والرضاعة

أخبري طبيبكِ إذا كنتِ حاملًا أو تحاولين أن تحملي أو ترضعين رضاعة طبيعية قبل استخدام هذا الدواء.

 

الحمل

لا تستخدمي ميثوتريكسات أثناء الحمل إلا إذا وصفه لكِ طبيبكِ لعلاج الأورام. يمكن أن يتسبب ميثوتريكسات في حدوث تشوهات ولادية أو ضرر للجنين أو إجهاض. وهو مرتبط بالتسبب في حدوث تشوهات في الجمجمة والوجه والقلب والأوعية الدموية والدماغ والأطراف. لذا من المهم جدًا ألا يتم إعطاء ميثوتريكسات للسيدات الحوامل أو اللاتي تخططن للإنجاب إلا إذا كان سيستخدم في علاج الأورام.

 

بالنسبة لدواعي الاستعمال غير المتعلقة بالأورام، يجب استبعاد احتمال الحمل في السيدات في سن الإنجاب، على سبيل المثال عن طريق إجراء اختبارات الحمل، قبل بدء العلاج.

 

لا تستخدمي ميثوتريكسات إذا كنتِ تحاولين أن تصبحي حاملًا. يجب عليكِ تجنب الحمل أثناء العلاج بميثوتريكسات ولمدة ٦ أشهر على الأقل بعد نهاية العلاج. لذلك يجب عليكِ التأكد من استخدام وسائل منع حمل فعالة طوال هذه المدة (انظري أيضًا قسم "الاحتياطات عند استعمال ميثوتريكسات").

 

إذا أصبحتِ حاملًا أثناء تلقي العلاج أو كنتِ تشكين في ذلك، فتحدثي إلى طبيبكِ في أقرب وقت ممكن. إذا أصبحتِ حاملًا بالفعل أثناء تلقي العلاج، ينبغي أن يتم تقديم المشورة لكِ بشأن خطر حدوث آثار ضارة لطفلكِ خلال العلاج. إذا كنتِ ترغبين في الحمل، ينبغي لكِ التحدث مع طبيبكِ الذي قد يحيلكِ إلى متخصص للحصول على المشورة قبل البدء المخطط للعلاج.

 

ينبغي على الأمهات عدم القيام بالرضاعة الطبيعية أثناء استمرار العلاج بميثوتريكسات.

 

الخصوبة في الرجال

لا تشير الأدلة المتاحة إلى زيادة خطر حدوث تشوهات أو إجهاض إذا كان الأب يتلقى ميثوتريكسات بجرعة أقل من ٣٠ ملجم/أسبوع. ومع ذلك، لا يمكن استبعاد الخطر تمامًا، ولا توجد معلومات تخص الجرعات الأعلى من ميثوتريكسات. يمكن أن يكون لميثوتريكسات تأثيرات سمية جينيًا، مما يعني أن هذا الدواء قد يتسبب في حدوث طفرات جينية. يمكن أن يؤثر ميثوتريكسات على إنتاج الحيوانات المنوية المرتبط بإمكانية حدوث تشوهات ولادية.

 

ينبغي تجنب إنجاب طفل أوالتبرع بالسائل المنوي أثناء العلاج بميثوتريكسات ولمدة ۳ أشهر على الأقل بعد نهاية العلاج. نظرًا لأن العلاج بجرعات أعلى من ميثوتريكسات، المستخدم بشكل شائع في علاج السرطان، يمكن أن يسبب عقمًا وطفرات جينية، فقد يكون من الأفضل للمرضى الرجال الذين يتم علاجهم بجرعات أعلى من ٣٠ ملجم/أسبوع من ميثوتريكسات أن يفكروا في تجميد الحيوانات المنوية قبل بداية العلاج (انظر أيضًا قسم "الاحتياطات عند استعمال ميثوتريكسات").

 

استشيري طبيبكِ أو الصيدلي قبل تناول أي دواء.

 

تأثير حقن ميثوتريكسات على القيادة واستخدام الآلات

لا تقم بالقيادة أو استخدام الآلات إذا أصبت بأي آثار جانبية (مثل الدوار، أو النعاس، أو تغيم الرؤية) يمكن أن تقلل من قدرتك على فعل هذا.

 

معلومات هامة حول بعض مكونات حقن ميثوتريكسات

تحتوي حقن ميثوتريكسات على الصوديوم

يحتوي ميثوتريكسات بتركيز ٥٠ ملجم/٢ مل على أقل من ١ مليمول من الصوديوم (٢٣ ملجم) في كل قارورة، أي أنه "خالٍ من الصوديوم" أساسًا.

 

يحتوي ميثوتريكسات بتركيز ٥٠٠ ملجم/٢٠ مل على ٤١,١ ملجم من الصوديوم (المكون الرئيسي لملح الطعام/المائدة) في كل قارورة. وهو ما يعادل ٢,٠٦ ٪ من الحد الأقصى الموصى به للحصة الغذائية اليومية من الصوديوم للبالغين.
 

 

 

 

https://localhost:44358/Dashboard

يمكن أن يتم إعطاؤك هذا الدواء بواسطة الحقن داخل أحد الأوردة (الحقن عن طريق الوريد) أو داخل عضلة (الحقن عن طريق العضل) أو داخل شريان (الحقن عن طريق الشريان) أو داخل الحبل الشوكي (الحقن داخل القراب)*. يمكن أيضًا أن يتم إعطاؤه عن طريق التسريب (التقطير) داخل أحد الأوردة. يمكن أن يتم تخفيفه قبل إعطائه.

 

* من بين الأشكال المتاحة (انظر القسم ٦)، فقط قارورة الـ٥٠ ملجم/٢ مل هي الملائمة للحقن داخل القراب.

 

الجرعة الموصى بها

سوف يحسب طبيبك الجرعة التي تلائمك من حقن ميثوتريكسات ومعدل إعطائها لك.

 

سوف تعتمد جرعة الدواء المعطاة لك على المرض الذي يتم علاجه، وعلى حالتك الطبية، وعمرك، وحجم جسمك، والكفاءة التي تعمل بها كليتاك.

 

الجرعة في حالات الصدفية الشديدة:

يتم إعطاء ميثوتريكسات مرة واحدة فقط في الأسبوع.

 

تحذير هام متعلق بجرعة حقن ميثوتريكسات:

 

استخدم حقن ميثوتريكسات مرة واحدة في الأسبوع فقط لعلاج الصدفية. قد يكون استخدام ميثوتريكسات أكثر من اللازم مميتًا. يرجى قراءة القسم ٣ من هذه النشرة بعناية شديدة. إذا كانت لديك أي أسئلة، يرجى التحدث مع طبيبك أو الصيدلي قبل استخدام هذا الدواء.

 

الجرعة الزائدة من حقن ميثوتريكسات

سيتم إعطاء هذا الدواء لك في مستشفى، وتحت إشراف طبيب. ومن غير المرجح أن يتم إعطاؤك كمية أكبر أو أقل بكثير مما ينبغي، ومع ذلك، أخبر طبيبك أو الممرضة إذا كانت لديك أي مخاوف.

 

 

يعد ميثوتريكسات دواءً شديد السمية، وقد توفي بعض المرضى أو أصبحوا مريضين للغاية أثناء العلاج به. ينبغي عليك أثناء العلاج التنبه لأي آثار جانبية وإبلاغ الطبيب عنها.

 

إذا حدث أي مما يلي، فأخبر طبيبك على الفور:

·            تفاعل حساسية شديد - قد تصاب بطفح جلدي مفاجئ مثير للحكة وتورم في اليدين أو القدمين أو الكاحلين أو الوجه أو الشفتين أو الفم أو الحلق (مما قد يسبب صعوبة في البلع أو التنفس) وقد تشعر بأنك على وشك الإصابة بالإغماء

·            التهاب الرئة المصحوب بعدم القدرة على التنفس - يمكن أن تصاب بسعال مستمر أو بألم أو صعوبة في التنفس أو أن تصبح غير قادر على التنفس. قد يكون هذا مرتبطًا بتغيرات في نوع محدد من خلايا الدم البيضاء في دمك.

·            بصق أو سعال الدم*

·            أعراض العدوى مثل الحمى، القشعريرة، التوجع، التهاب الحلق

·            النزيف غير المتوقع، مثل: نزيف اللثة أو وجود دم في البول أو القيء أو ظهور كدمات غير متوقعة أو أوعية دموية متقطعة (أوردة متقطعة)

·            البراز الأسود القطراني

·            التهاب الفم، خصوصًا إذا كان لديك عدد من القرح أو التبثرات داخل الفم أو على اللسان

·            الطفح الجلدي أو التبثرات على أسطح العينين أو الأنف أو المهبل أو فتحة الشرج

·            الإسهال

·            السكتة الدماغية/الضعف في أحد جانبي الجسم

·            الشعور بضعف في الساقين ينتشر إلى الأطراف العلوية والوجه، والذي قد يؤدي بدوره إلى الإصابة بالشلل

·            ألم البطن، البراز الدهني، القيء

·            ألم الصدر (والذي قد يكون نتيجة لمشكلات القلب أو الرئتين)

 

*(تم الإبلاغ عن حدوث تلك الأعراض الجانبية عند استخدام ميثوتريكسات مع المرضى الذين يعانون من أمراض الروماتيزم الكامنة)

 

تُعد هذه الآثار الجانبية خطيرة. وقد تحتاج إلى رعاية طبية طارئة.

 

إذا حدث أي مما يلي، فأخبر طبيبك في أقرب وقت ممكن:

·            انخفاض ضغط الدم (قد تشعر بالإغماء)

·            نوبات

·            تغيم الرؤية

·            دوار

·            صعوبة/فقدان القدرة على الكلام

·            ضعف العضلات

·            قد تشعر بأنك تحتاج إلى أن تشرب بمعدل أكثر من المعتاد (السكري)

·            انكسار العظام بسهولة غير طبيعية (هشاشة العظام)

·            ألم أو احمرار في الأوعية الدموية (التهاب الأوعية الدموية)

·            حكة أو ظهور رقع فاتحة اللون على الجلد، كدمات، دمامل

·            زيادة حساسية الجلد تجاه ضوء الشمس عن المستوى الطبيعي. وقد تصاب بالطفح الجلدي، أو احمرار الجلد، أو التورم، أو حروق الشمس الشديدة

·            حب الشباب

·            اصفرار لون الجلد وبياض العينين (يرقان)

·            ألم في المعدة أو العانة أو البطن

·            قد تحتاج إلى التبول بشكل أكثر من العادي، ما قد يكون مؤلمًا (التهاب المثانة)

·            صداع

·            نعاس

·            شعور بالتعب أو التوعك بشكل عام

·            انخفاض الشهية، الشعور بالرغبة في التقيؤ أو التقيؤ بالفعل

·            عدم انتظام الدورة الشهرية لدى السيدات (قد تتوقف الدورة الشهرية تمامًا)

·            تساقط الشعر

·            آثار على التعلم والذاكرة

·            رنين في الأذن

·            ألم في المفاصل والعضلات

·            جلطات دموية تسبب الألم أو التورم أو الاحمرار (دماغية، أو في وريد عميق، أو في الوريد الشبكي، أو في الوريد الشرياني)

·            تغيرات مزاجية

·            التهاب الرئتين مما يسبب عدم القدرة على التنفس والسعال وارتفاع درجة الحرارة، التهاب رئوي

·            القوباء (الحزام الناري)

·            نزيف من الرئتين (معدل التكرارغير معروف)*

·            اضطرابات التكاثر الليمفاوي (النمو المفرط لخلايا الدم البيضاء) (معدل التكرار نادر جدًا)

·            تضرر عظام الفك (بسبب النمو المفرط لخلايا الدم البيضاء) (معدل التكرار غير معروف)

·            احمرار وتقشر الجلد (معدل التكرار غير معروف)

·            شعور بالخدر أو الوخز، انخفاض الحساسية تجاه المثيرات إلى الأقل من الطبيعي (معدل التكرار نادر جدًا)

·            تورم (معدل التكرار غير معروف)

·            تفاعل في موضع الحقن (معدل التكرار غير معروف)**

·            بقع على الجلد بلون أحمر داكن أو أسود حول موضع الحقن، وغالبًا ما يصاحبها إحساس بالألم (نخر موضع الحقن) (معدل التكرار غير معروف)**

 

*(تم الإبلاغ عن حدوث تلك الأعراض الجانبية عند استخدام ميثوتريكسات مع المرضى الذين يعانون من أمراض الروماتيزم الكامنة). **(عن طريق الحقن فقط).

 

يمكن أن تظهر بعض الآثار الجانبية المختلفة بعد الحقن داخل الحبل الشوكي. وهي

·            صداع

·            ألم الظهر أو الكتف

·            صعوبة في الانحناء برأسك لأسفل

·            حمى

·            ضعف أو شلل مؤقت

·            مشكلات في جزء محدد من الدماغ، الأمر الذي يؤدي إلى الارتجاف أو فقدان الاتزان أو الترنح.

·            تهيج وارتباك

·            تيبس

·            نوبات

·            ارتباك وفقدان للذاكرة

·            نعاس

·            غيبوبة

·            الوفاة

 

يمكن أن يؤدي ميثوتريكسات إلى مشكلات في دمك وكبدك وكليتيك. سوف يقوم طبيبك بسحب عينات دم لتفقد هذه المشكلات وقد يطلب منك الخضوع لعملية من أجل أخذ عينة صغيرة من كبدك.

 

إذا ما تفاقمت شدة أي من الآثار الجانبية بشكل خطير أو لاحظت ظهور أي آثار جانبية غير واردة في هذه النشرة، يرجى إخبار طبيبك.

 

الآثار على الخصوبة

يمكن للعلاج بميثوتريكسات أن يقلل من الخصوبة لدى الرجال والسيدات. يعتقد أن الخصوبة تعود إلى حالتها الطبيعية بعد إيقاف العلاج بميثوتريكسات. أخبر طبيبك إذا كانت لديك مخاوف.

 

تفاعل ضار للعقار بعد التسويق: سرطان الجلد غير الميلانيني بوصفه حدثًا ضارًا نادرًا جدًا للعقار.

 

الإبلاغ عن الأعراض الجانبية:

إذا أصبت بأي آثار جانبية، فتحدث إلى طبيبك أو الصيدلي. يتضمن ذلك أي آثار جانبية محتملة غير مدرجة في هذه النشرة. بالإبلاغ عن الآثار الجانبية، يمكنك المساعدة في توفير المزيد من المعلومات حول سلامة هذا الدواء.

 

للإبلاغ عن الأعراض الجانبية

 

•       المملكة العربية السعودية

 

المركز الوطني للتيقظ الدوائي

·       مركز الاتصال الموحد: ١٩٩٩٩

·       البريد الإلكتروني: npc.drug@sfda.gov.sa

·       الموقع الإلكتروني: https://ade.sfda.gov.sa

 

•       دول الخليج الأخرى

 

-        الرجاء الاتصال بالمؤسسات والهيئات الوطنية في كل دولة.

 

 

 

 

يُحفظ بعيدًا عن متناول ومرأى الأطفال.

 

الصلاحية

يجب عدم استخدام هذا الدواء بعد تاريخ انتهاء الصلاحية المدون على ملصق القارورة والعبوة الكرتونية بعد الرمز "EXP". وفي حالة ذكر الشهر والسنة فقط، فيشير تاريخ انتهاء الصلاحية إلى آخر يوم من الشهر المذكور.

 

التخزين

ينبغي الاحتفاظ بالقوارير في العبوة الكرتونية الخارجية لحمايتها من الضوء، وتخزينها في درجة حرارة أقل من ٢٥ درجة مئوية. ينبغي عدم تجميد القوارير.

يجب عدم تخزين الكميات غير المستخدمة من القوارير المفتوحة للاستخدام في وقت لاحق.

ينبغي استخدام الكميات التي تم تجهيزها للتسريب على الفور، ولكن إذا لم يكن ذلك ممكنًا، يمكن في ظروف معينة تخزينها لمدة تصل إلى ٣٠ يومًا في البراد (الثلاجة) شريطة تحضيرها بطريقة تستبعد التلوث بالميكروبات.

 

المادة الفعالة هي ميثوتريكسات. يحتوي كل ملليلتر (مل) من المحلول على ٢٥ مليجرام (ملجم) من ميثوتريكسات.

المكونات الأخرى هي كلوريد الصوديوم، وهيدروكسيد الصوديوم (انظر القسم ٢ "تحتوي حقن ميثوتريكسات على الصوديوم")، وماء للحقن.

حقن ميثوتريكسات هي محلول صاف أًصفر اللون للحقن يتم تزويده في حاويات زجاجية تدعى قوارير.

 

يمكن توفير الدواء في عبوات تحتوي على:

•           ٥ قوارير × ٥٠ ملجم/٢ مل

•           قارورة واحدة × ٥٠٠ ملجم/٢٠ مل

مالك تصريح التسويق

Hospira UK limited, Horizon Honey Lane, Hurley, Maidenhead, SL6 6RJ, United Kingdom.

 

المصنع:

Hospira Australia Pty Ltd  1-5, 7-23 and 25-39 Lexia Place
 MULGRAVE, VIC 3170, Australia.

 

أكتوبر/تشرين الأول ٢٠٢۳
 Read this leaflet carefully before you start using this product as it contains important information for you

Methotrexate 25 mg/ml Injection

Each ml of solution contains 25 mg methotrexate (sodium salt formed in situ) Each vial of 2 ml of solution contains 50 mg methotrexate (sodium salt formed in situ) Each vial of 20 ml of solution contains 500 mg methotrexate (sodium salt formed in situ) Excipient with known effect Methotrexate 500 mg/20 ml contains 41.1 mg sodium per vial For the full list of excipients, see section 6.1.

Solution for Injection Vials containing a clear yellow solution

Methotrexate is indicated in the treatment of neoplastic disease, such as trophoblastic neoplasms and leukaemia, and the symptomatic treatment of severe recalcitrant disabling psoriasis which is not adequately responsive to other forms of therapy.

 


Methotrexate should only be prescribed by physicians with expertise in the use of methotrexate and a full understanding of the risks of methotrexate therapy.

 

The prescriber should ensure that patients or their carers will be able to comply with the once weekly regimen.

 

Important warning about the dosage of Methotrexate

 

In the treatment of psoriasis, Methotrexate must only be used once a week. Dosage errors in the use of Methotrexate can result in serious adverse reactions, including death. Please read this section of the summary of product characteristics very carefully.

 

Adults and children

 

Antineoplastic Chemotherapy

 

Methotrexate is active orally and parenterally. Methotrexate Injection may be given by the intramuscular, intravenous, intraarterial or intrathecal routes. 

 

Note: Only the 50 mg/2 ml presentation should be used for the intrathecal route of administration to prevent accidental overdose.

 

Dosage is related to the patient's body weight or surface area. Methotrexate has been used with beneficial effect in a wide variety of neoplastic diseases, alone and in combination with other cytotoxic agents.

 

Choriocarcinoma and Similar Trophoblastic Diseases

 

Methotrexate is administered orally or intramuscularly in doses of 15-30 mg daily for a 5 day course.  Such courses may be repeated 3-5 times as required, with rest periods of one or more weeks interposed between courses until any manifesting toxic symptoms subside.

 

The effectiveness of therapy can be evaluated by 24 hours quantitative analysis of urinary chorionic gonadotrophin hormone (HCG). Combination therapy with other cytotoxic drugs, has also been reported as useful.

 

Hydatidiform mole may precede or be followed by choriocarcinoma, and methotrexate has been used in similar doses for the treatment of hydatidiform mole and chorioadenoma destruens.

 

Breast Carcinoma

 

Prolonged cyclic combination with cyclophosphamide, methotrexate and fluorouracil has given good results when used as adjuvant treatment to radical mastectomy in primary breast cancer with positive axillary lymph nodes. Methotrexate dosage was 40 mg/m2 intravenously on the first and eighth days.

 

Leukaemia

 

Acute granulocytic leukaemia is rare in children but common in adults and this form of leukaemia responds poorly to chemotherapy.

 

Methotrexate is not generally a drug of choice for induction of remission of lymphoblastic leukaemia. Oral methotrexate dosage 3.3 mg/m2 daily, and prednisolone 40-60 mg/m2 daily for 4-6 weeks has been used. After a remission is attained, methotrexate in a maintenance dosage of 20-30 mg/m2 orally or by intramuscular injection has been administered twice weekly. Twice weekly doses appear to be more effective than daily drug administration. Alternatively, 2.5 mg/kg has been administered intravenously every 14 days.

 

Meningeal Leukaemia

 

Some patients with leukaemia are subject to leukaemic invasions of the central nervous system and the CSF should be examined in all leukaemia patients.

 

Passage of methotrexate from blood to the cerebrospinal fluid is minimal and for adequate therapy the drug should be administered intrathecally. Methotrexate may be given in a prophylactic regimen in all cases of lymphocytic leukaemia. The dose of intrathecal Methotrexate is constant regardless of age or body surface area in patients over the age of 3 years of age, the maximum intrathecal dose should be 12 mg in such patients. Patients under the age of 3 years should be treated in accordance with combination chemotherapy protocols. The administration is at weekly intervals and is usually repeated until the cell count of cerebrospinal fluid returns to normal. At this point one additional dose is advised. Large doses may cause convulsions and untoward side effects may occur as with any intrathecal injection, and are commonly neurological in character.

 

Note: Only the 50 mg/2 ml presentation should be used for the intrathecal route of administration to prevent accidental overdose.

 

Lymphomas

 

In Burkitt's Tumour, stages 1-2, methotrexate has prolonged remissions in some cases. Recommended dosage is 10-25 mg per day orally for 4 to 8 days. In stage 3, methotrexate is commonly given concomitantly with other antitumour agents. Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods, and in stage 3 they respond to combined drug therapy with methotrexate given in doses of 0.625 mg to 2.5 mg/kg daily. Hodgkin's disease responds poorly to methotrexate and to most types of chemotherapy.

 

Mycosis Fungoides

 

Therapy with methotrexate appears to produce clinical remissions in one half of the cases treated. Recommended dosage is usually 2.5 to 10 mg daily by mouth for weeks or months and dosage should be adjusted according to the patient's response and haematological monitoring. Methotrexate has also been given intramuscularly in doses of 50 mg once weekly or 25 mg twice weekly.

 

Use in patients with renal impairment – dose adjustments

Methotrexate is excreted to a significant extent by the kidneys, and therefore should be used with caution in patients with impaired renal function (see sections 4.3 and 4.4). The health care provider may need to adjust the dose to prevent accumulation of drug. The table below provided recommended starting doses in renally impaired patients; dosing may need further adjustment due to wide intersubject pK variability.

 

Table 1 a.   Dose adjustments for methotrexate doses <100 mg/m2 in patients with renal impairment

Creatinine Clearance (ml/min)

% of dose to Administer

>60

100

30-59

50

<30

Methotrexate must not be administered.

Table 1 b.  Dose adjustments for methotrexate doses >100 mg/m2 in patients with renal impairment

Creatinine Clearance (ml/min)

% of dose to Administer

>80

100

= ~80

75

= ~60

63

<60

Methotrexate must not be administered.

   

 

Psoriasis Chemotherapy

 

Cases of severe uncontrolled psoriasis, unresponsive to conventional therapy, have responded to weekly single, oral, intramuscular or intravenous doses of 10-25 mg per week, and adjusted according to the patient's response. An initial test dose one week prior to initiation of therapy is recommended to detect any idiosyncrasy. A suggested dose range is 5-10 mg.

 

The prescriber should specify the day of intake on the prescription.

 

The patient should be fully informed of the risks involved and the clinician should pay particular attention to the appearance of liver toxicity by carrying out liver function tests before starting methotrexate treatment, and repeating these at 2 to 4 month intervals during therapy. The aim of therapy should be to reduce the dose to the lowest possible level with the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy which should be encouraged.

 

Use in the elderly

Methotrexate should be used with extreme caution in elderly patients. A reduction in dosage should be considered.


Methotrexate is contraindicated in: Patients with significantly impaired renal function (creatinine clearance less than 30 ml/min) for methotrexate doses <100 mg/m2, and moderate renal impairment (creatinine clearance less than 60 ml/min) for methotrexate doses >100 mg/m2 (see section 4.2). Patients with significantly impaired hepatic function Patients with pre-existing blood dyscrasias, such as significant marrow hypoplasia, leukopenia, thrombocytopenia or anaemia. Patients with active infections. Patients with overt or laboratory evidence of immunodeficiency syndrome(s). Methotrexate is contraindicated in pregnancy (see section 4.6). Because of the potential for serious adverse reactions from methotrexate in breast fed infants, breast feeding is contraindicated in women taking methotrexate (see section 4.6). Patients with a known hypersensitivity to methotrexate or any of the other excipients listed in 6.1.

WARNINGS

 

Methotrexate must be used only by physicians experienced in antimetabolite chemotherapy.

 

Because of the possibility of fatal or severe toxic reactions, the patient should be fully informed by the physician of the risks involved and be under his constant supervision.

 

The prescriber should specify the day of intake on the prescription. The prescriber should make sure patients understand that methotrexate should only be taken once a week. Patients should be instructed on the importance of adhering to the once-weekly intakes.

 

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported. Symptoms typically include dyspnoea, cough (especially a dry non-productive cough), thoracic pain, and fever for which patients should be monitored at each follow-up visit. Patients should be informed of the risk of pneumonitis and advised to contact their doctor immediately should they develop persistent cough or dyspnoea.

 

In addition, pulmonary alveolar haemorrhage has been reported with methotrexate used in rheumatologic and related indications. This event may also be associated with vasculitis and other comorbidities. Prompt investigations should be considered when pulmonary alveolar haemorrhage is suspected to confirm the diagnosis.

 

Methotrexate should be withdrawn from patients with pulmonary symptoms and a thorough investigation should be made to exclude infection. If methotrexate induced lung disease is suspected treatment with corticosteroids should be initiated and treatment with methotrexate should not be restarted.

When a patient presents with pulmonary symptoms, the possibility of Pneumocystis carinii pneumonia should be considered.

Methotrexate has the potential for serious, sometimes fatal toxicity. The toxic effects may be related in frequency and severity to the dose or frequency of administration but have been seen at all doses. Because the toxic reactions can occur at any time during therapy, the patients have to be observed closely and must be informed of early signs and symptoms of toxicity.

 

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive medication. PML can be fatal and should be considered in the differential diagnosis in immunosuppressed patients with new onset or worsening neurological symptoms.

 

Use caution when administering high-dose methotrexate to patients receiving proton pump inhibitor (PPI) therapy. Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs, such as omeprazole, esomeprazole, and pantoprazole, with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted.

 

Deaths have been reported with the use of methotrexate in the treatment of psoriasis.

 

In the treatment of psoriasis, methotrexate should be restricted to severe recalcitrant, disabling psoriasis which is not adequately responsive to other forms of therapy, but only when the diagnosis has been established by biopsy and/or after dermatological consultation.

 

1.  Full blood counts should be closely monitored before, during and after treatment. If a clinically significant drop in white-cell or platelet count develops, methotrexate should be withdrawn immediately. Patients should be advised to report all symptoms or signs suggestive of infection.

 

2.  Methotrexate may be hepatotoxic, particularly at high dosage or with prolonged therapy.  Liver atrophy, necrosis, cirrhosis, fatty changes, and periportal fibrosis have been reported. 

 

Liver function tests: Treatment should not be initiated or should be discontinued if there are persistent or significant abnormalities in liver function tests, other non-invasive investigations of hepatic fibrosis, or liver biopsies.

 

Temporary increases in transaminases to two or three times the upper limit of normal have been reported in patients at a frequency of 13-20 %. Persistent elevation of liver enzymes and/or decrease in serum albumin may be indicative for severe hepatotoxicity. In the event of a persistent increase in liver enzymes, consideration should be given to reducing the dose or discontinuing therapy.

 

Histological changes, fibrosis and more rarely liver cirrhosis may not be preceded by abnormal liver function tests. There are instances in cirrhosis where transaminases are normal. Therefore, non-invasive diagnostic methods for monitoring of liver condition should be considered, in addition to liver function tests. Liver biopsy should be considered on an individual basis taking into account the patient’s comorbidities, medical history and the risks related to biopsy. Risk factors for hepatotoxicity include excessive prior alcohol consumption, persistent elevation of liver enzymes, history of liver disease, family history of hereditary liver disorders, diabetes mellitus, obesity and previous contact with hepatotoxic drugs or chemicals and prolonged methotrexate treatment.

 

Additional hepatotoxic medicinal products should not be given during treatment with methotrexate unless clearly necessary. Alcohol consumption should be avoided (see sections 4.3 and 4.5). Closer monitoring of liver enzymes should be undertaken in patients concomitantly taking other hepatotoxic medicinal products.

 

Increased caution should be exercised in patients with insulin-dependent diabetes mellitus, as during methotrexate therapy, liver cirrhosis developed in isolated cases without any elevation of transaminases.

 

3.  Methotrexate has been shown to be teratogenic; it has caused foetal death and/or congenital anomalies. Therefore it is not recommended in women of childbearing potential unless there is appropriate medical evidence that the benefits can be expected to outweigh the considered risks.  Pregnant psoriatic patients should not receive methotrexate.

 

4.  Methotrexate therapy in patients with impaired renal function should be undertaken with extreme caution because impairment of renal function will decrease methotrexate elimination.

 

Renal function should be monitored by renal function tests and urinalyses. If serum creatinine levels are increased, the dose should be reduced. If creatinine clearance is less than 30 ml/min, treatment with methotrexate should not be given. If creatinine clearance is less than 60 ml/min, methotrexate doses >100 mg/m2 not be given (see section 4.2 and 4.3).

 

Treatment with methotrexate doses of >100 mg/m2 should not be initiated at urinary pH values of less than 7.0. Alkalinisation of the urine must be tested by repeated pH monitoring (value greater than or equal to 6.8) for at least the first 24 hours after the administration of methotrexate is started.

 

Methotrexate may cause renal damage that may lead to acute renal failure. Close attention to renal function including adequate hydration, urine alkalinization, and measurement of serum methotrexate and renal function are recommended.

 

As methotrexate is eliminated mainly via the kidneys, increased concentrations are to be expected in the presence of renal impairment, which may result in severe adverse reactions.

 

If there is the possibility of renal impairment (e.g. in elderly subjects), monitoring should take place at shorter intervals. This applies in particular when medicinal products that affect the elimination of methotrexate, or that cause kidney damage (e.g. NSAIDs) or that can potentially lead to impairment of haematopoiesis, are administered concomitantly.

 

If risk factors such as renal function disorders, including mild renal impairment, are present, combined administration with NSAIDs is not recommended. Dehydration may also intensify the toxicity of methotrexate.

 

Concomitant use of proton pump inhibitors (PPIs) and high dose methotrexate should be avoided, especially in patients with renal impairment.

 

5.  Diarrhoea and ulcerative stomatitis are frequent toxic effects and require interruption of therapy, otherwise haemorrhagic enteritis and death from intestinal perforation may occur.

 

6.  Methotrexate affects gametogenesis during the period of its administration and may result in decreased fertility which is thought to be reversible on discontinuation of therapy. Conception should be avoided during the period of methotrexate administration and for at least 6 months thereafter. Patients and their partners should be advised to this effect.

 

7.  Methotrexate has some immunosuppressive activity and immunological responses to concurrent vaccination may be decreased. The immunosuppressive effect of methotrexate should be taken into account when immune responses of patients are important or essential. Immunisation with live virus vaccines is generally not recommended.

8.  Pleural effusions and ascites should be drained prior to initiation of methotrexate therapy.

 

9.   Deaths have been reported with the use of methotrexate. Serious adverse reactions including deaths have been reported with concomitant administration of methotrexate (usually in high doses) along with some non-steroidal anti-inflammatory drugs (NSAIDs).

 

10.Concomitant administration of folate antagonists such as trimethoprim/sulphamethoxazole has been reported to cause an acute megaloblastic pancytopenia in rare instances.

 

11. Systemic toxicity may occur following intrathecal administration. Blood counts should be monitored closely.

 

12. A chest X-ray is recommended prior to initiation of methotrexate therapy.

 

13. If acute methotrexate toxicity occurs, patients may require folinic acid.

 

14. Severe, occasionally fatal, cutaneous or sensitivity reactions (e.g., toxic epidermic necrolysis, Stevens-Johnson syndrome, exfoliative dermatitis, skin necrosis, erythema multiforme, vasculitis and extensive herpetiform skin eruptions) may occur after the administration of methotrexate and recovery ensured mostly after discontinuation of the therapy.

 

PRECAUTIONS

 

Methotrexate has a high potential toxicity, usually dose related, and should be used only by physicians experienced in antimetabolite chemotherapy, in patients under their constant supervision.  The physician should be familiar with the various characteristics of the drug and its established clinical usage.

 

Before beginning methotrexate therapy or reinstituting methotrexate after a rest period, assessment of renal function, liver function and blood elements should be made by history, physical examination and laboratory tests.

 

It should be noted that intrathecal doses are transported into the cardiovascular system and may give rise to systemic toxicity. Systemic toxicity of methotrexate may also be enhanced in patients with renal dysfunction, ascites, or other effusions due to prolongation of serum half-life.

 

In rare cases, following intrathecal administration, a tumour lysis syndrome has been observed.

 

Carcinogenesis, mutagenesis, and impairment of fertility: Animal carcinogenicity studies have demonstrated methotrexate to be free of carcinogenic potential. Although methotrexate has been reported to cause chromosomal damage to animal somatic cells and bone marrow cells in humans, these effects are transient and reversible. In patients treated with methotrexate, evidence is insufficient to permit conclusive evaluation of any increased risk of neoplasia.

 

Fertility and reproduction

Fertility

Methotrexate has been reported to cause impairment of fertility, oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, affecting spermatogenesis and oogenesis during the period of its administration - effects that appear to be reversible on discontinuing therapy. In addition, methotrexate causes embryotoxicity, abortion and foetal defects in humans. 

 

Teratogenicity – Reproductive risk: Methotrexate causes embryotoxicity, abortion and foetal malformations in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential (see section 4.6), the absence of pregnancy must be confirmed before Methotrexate is used. If women of a sexually mature age are treated, effective contraception must be used during treatment and for at least six months after.

 

For contraception advice for men see section 4.6.

 

Patients undergoing therapy should be subject to appropriate supervision so that signs or symptoms of possible toxic effects or adverse reactions may be detected and evaluated with minimal delay. Pre-treatment and periodic haematological studies are essential to the use of methotrexate in chemotherapy because of its common effect of haematopoietic suppression.  This may occur abruptly and on apparent safe dosage, and any profound drop in blood cell count indicates immediate stopping of the drug and appropriate therapy. In patients with malignant disease who have pre-existing bone marrow aplasia, leukopenia, thrombocytopenia or anaemia, methotrexate should be used with caution, if at all.

 

In general, the following laboratory tests are recommended as part of essential clinical evaluation and appropriate monitoring of patients chosen for or receiving methotrexate therapy: complete haemogram; haematocrit; urinalysis; renal function tests; liver function tests and chest X-ray.

 

The purpose is to determine any existing organ dysfunction or system impairment. The tests should be performed prior to therapy, at appropriate periods during therapy and after termination of therapy.

 

Methotrexate is bound in part to serum albumin after absorption, and toxicity may be increased because of displacement by certain drugs such as salicylates, sulphonamides, phenytoin, and some antibacterials such as tetracycline, chloramphenicol and para-aminobenzoic acid. These drugs, especially salicylates and sulphonamides, whether antibacterial, hypoglycaemic or diuretic, should not be given concurrently until the significance of these findings is established.

 

Vitamin preparations containing folic acid or its derivatives may alter response to methotrexate.

 

Methotrexate should be used with extreme caution in the presence of infection, peptic ulcer, ulcerative colitis, debility, and in extreme youth and old age. If profound leukopenia occurs during therapy, bacterial infection may occur or become a threat. Cessation of the drug and appropriate antibiotic therapy is usually indicated. In severe bone marrow depression, blood or platelet transfusions may be necessary.

 

Since it is reported that methotrexate may have an immunosuppressive action, this factor must be taken into consideration in evaluating the use of the drug where immune responses in a patient may be important or essential.

 

In all instances where the use of methotrexate is considered for chemotherapy, the physician must evaluate the need and usefulness of the drug against the risks of toxic effects or adverse reactions. Most such adverse reactions are reversible if detected early. When such effects or reactions do occur, the drug should be reduced in dosage or discontinued and appropriate corrective measures should be taken according to the clinical judgement of the physician.  Reinstitution of methotrexate therapy should be carried out with caution, with adequate consideration of further need for the drug and alertness as to the possible recurrence of toxicity. 

 

Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.

 

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking methotrexate (see section 4.8). Exposure to intense sunlight or to UV rays should be avoided. Patients should use a sun-protection product with a high protection factor.

 

Excipient information

Methotrexate 50 mg/2 ml contain less than 1 mmol sodium (23 mg) per vial, that is to say essentially ‘sodium free’.

 

Methotrexate 500 mg/20 ml contains 41.1 mg sodium per vial, equivalent to 2.06% of the WHO recommended maximum daily intake of 2 g sodium for an adult.


Methotrexate is extensively protein bound and may be displaced by certain drugs such as salicylates, hypoglycaemics, diuretics, sulphonamides, diphenylhydantoins, tetracyclines, chloramphenicol and p-aminobenzoic acid, and the acidic anti-inflammatory agents, so causing a potential for increased toxicity when used concurrently. 

 

Concomitant use of other drugs with nephrotoxic or hepatotoxic potential (including alcohol) should be avoided. 

 

Vitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate.

 

Caution should be used when NSAIDs and salicylates are administered concomitantly with methotrexate. These drugs have been reported to reduce the tubular secretion of methotrexate and thereby may enhance its toxicity. Concomitant use of NSAIDs and salicylates has been associated with fatal methotrexate toxicity.

 

However, patients using constant dosage regimens of NSAIDs have received concurrent doses of methotrexate without problems observed. 

 

Treatment with more than one DMARD in various regimens is being tried but there is little evidence available to assess benefit. A meta-analysis of 5 different combinations of DMARDs demonstrated that although efficacy might be greater than single DMARDs, toxicity was also increased.

 

Renal tubular transport is also diminished by probenecid and penicillins; use of these with methotrexate should be carefully monitored.

 

A potential interaction may exist between methotrexate and proton-pump inhibitors (e.g. omeprazole, pantoprazole). Omeprazole may inhibit methotrexate clearance resulting in potentially toxic methotrexate levels.

 

Severe bone marrow depression has been reported following the concurrent use of methotrexate and co-trimoxazole or trimethoprim. Concurrent use should probably be avoided.

 

The use of nitrous oxide potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression and stomatitis and in cases of intrathecal administration increased severe, unpredictable neurotoxicity. Whilst this effect can be reduced by administering calcium folinate, the concomitant use of nitrous oxide and methotrexate should be avoided.

 

An increased risk of hepatitis has been reported following the use of methotrexate and the acitretin metabolite, etretinate. Consequently, the concomitant use of methotrexate and acitretin should be avoided.

 

Methotrexate may increase the bioavailability of mercaptopurine by interference with first-pass metabolism.

 

Concomitant application of methotrexate and theophylline can reduce theophylline clearance.

 


Pregnancy

Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3).

 

Both men and women receiving methotrexate should be informed of the potential risk of adverse effects on reproduction. Women of childbearing potential should be fully informed of the potential hazard to the foetus should they become pregnant during methotrexate therapy. In cancer chemotherapy, methotrexate should not be used in pregnant women or women of childbearing potential who might become pregnant unless the potential benefits to the mother outweigh the possible risks to the foetus.

 

If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment and ultrasonography examinations should be performed to confirm normal foetal development.

 

In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to be teratogenic to humans; it has been reported to cause foetal death, miscarriages and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related).

 

Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and congenital malformations in case of exposure during pregnancy.

 

• Spontaneous abortions have been reported in 42.5% of pregnant women exposed to low-dose methotrexate treatment (less than 30 mg/week), compared to a reported rate of 22.5% in disease-matched patients treated with drugs other than methotrexate.

• Major birth defects occurred in 6.6% of live births in women exposed to low-dose methotrexate treatment (less than 30 mg/week) during pregnancy, compared to approximately 4% of live births in in disease-matched patients treated with drugs other than methotrexate.

 

Insufficient data is available for methotrexate exposure during pregnancy higher than 30 mg/week, but higher rates of spontaneous abortions and congenital malformations are expected, in particular at doses commonly used in oncologic indications.

 

When methotrexate was discontinued prior to conception, normal pregnancies have been reported. 

 

When used in oncological indications, methotrexate should not be administered during pregnancy in particular during the first trimester of pregnancy. In each individual case the benefit of treatment must be weighed up against the possible risk to the foetus. If the drug is used during pregnancy or if the patient becomes pregnant while taking methotrexate, the patient should be informed of the potential risk to the foetus.

 

Breast-Feeding

Methotrexate is distributed into breast milk. Because of the potential for serious adverse reactions to methotrexate in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

 

          Fertility

Methotrexate affects spermatogenesis and oogenesis and may decrease fertility.  Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans. These effects appear to be reversible after discontinuation of therapy in most cases. In oncologic indications, women who are planning to become pregnant are advised to consult a genetic counselling centre, if possible, prior to therapy and men should seek advice about the possibility of sperm preservation before starting therapy as methotrexate can be genotoxic at higher doses (see section 4.4).

 

          Women of childbearing potential/Contraception in females

Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning.

 

          Contraception in males

It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure.

 

As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 3 months after cessation of methotrexate. Men should not donate semen during therapy or for 3 months following discontinuation of methotrexate.


Not applicable


The most common adverse reactions include ulcerative stomatitis, leukopenia, nausea and abdominal distress. Although very rare, anaphylactic reactions to methotrexate have occurred.  Others reported are malaise, undue fatigue, chills and fever, dizziness and decreased resistance to infection.  In general, the incidence and severity of side effects are considered to be dose-related.  Adverse reactions as reported for the various systems are as follows:

 

Skin: Severe, occasionally fatal, dermatologic reactions including erythema multiforme, Stevens-Johnson syndrome, skin necrosis, epidermal necrolysis. Erythematous rashes, pruritus, urticaria, dermatitis, photosensitivity, pigmentary changes, alopecia, ecchymosis, telangiectasia, acne, furunculosis. Lesions of psoriasis may be aggravated by concomitant exposure to ultraviolet radiation. Skin ulceration in psoriatic patients and rarely painful erosion of psoriatic plaques have been reported. The recall phenomenon has been reported in both radiation and solar damaged skin. Skin exfoliation, dermatitis exfoliative (frequency not known). 

 

Blood: Bone marrow depression, leukopenia, thrombocytopenia, anaemia hypogammaglobulinaemia, haemorrhage from various sites, septicaemia, lymphoproliferative disorders (frequency very rare).

 

Alimentary System: Gingivitis, pharyngitis, stomatitis, mucostitis, anorexia, vomiting, diarrhoea, haematemesis, melaena, gastrointestinal ulceration and bleeding, pancreatitis, enteritis, hepatic toxicity resulting in active liver atrophy, necrosis, fatty metamorphosis, periportal fibrosis, or hepatic cirrhosis. In rare cases the effect of methotrexate on the intestinal mucosa has led to malabsorption or toxic megacolon.

 

Hepatic: Hepatic toxicity resulting in significant elevations of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, hepatitis, periportal fibrosis, or cirrhosis or death may occur, usually following chronic administration.

 

Urogenital System: Renal failure, azotaemia, cystitis, haematuria, defective oogenesis or spermatogenesis, transient oligospermia, menstrual dysfunction, infertility, abortion, foetal defects, severe nephropathy. Vaginitis, vaginal ulcers, cystitis, haematuria and nephropathy have also been reported.

 

Pulmonary System: Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur and deaths have been reported (see section 4.4). Acute pulmonary oedema has also been reported after oral and intrathecal use. Pulmonary fibrosis is rare. A syndrome consisting of pleuritic pain and pleural thickening has been reported following high doses. Frequency Not Known: Pulmonary alveolar haemorrhage*.

*(has been reported for methotrexate used in rheumatologic and related indications).

 

Nervous System Disorder: Headaches, drowsiness, blurred vision, aphasia, cognitive disorder, hemiparesis and convulsions have occurred possibly related to haemorrhage or to complications from intraarterial catheterization. Convulsion, paresis, Guillain-Barre syndrome and increased cerebrospinal fluid pressure have followed intrathecal administration.

 

Signs of neurotoxicity (meningeal irritation, transient or permanent paresis, encephalopathy) should be monitored following intrathecal administration of methotrexate.

 

Other nervous system disorders include, dysarthria, cranial nerve disorders, lethargy, irritability. Other reactions related to, or attributed to the use of methotrexate such as pneumonitis, metabolic changes, precipitation of diabetes, osteoporotic effects, abnormal changes in tissue cells and even sudden death have been reported.

 

There have been reports of leukoencephalopathy following intravenous methotrexate in high doses, or low doses following cranial-spinal radiation.

Paraesthesia, hypoaesthesia (frequency very rare).

Cardiac disorders: Pericarditis, pericardial effusion.

 

Ear disorders: Tinnitus.

 

Eye disorders: Conjunctivitis.

 

Infections and infestations: Opportunistic infections (sometimes fatal e.g. fatal sepsis) have also been reported in patients receiving methotrexate therapy for neoplastic and non-neoplastic diseases, Pneumocystis carinii pneumonia being the most common. Other reported infections include, pneumonia, nocardiosis, histoplasmosis, cryptococcosis, Herpes Zoster, Herpes Simplex, hepatitis and cytomegalovirus infection, including cytomegaloviral pneumonia.

 

Musculoskeletal and connective tissue disorders: Arthralgia/myalgia, Osteonecrosis of jaw (secondary to lymphoproliferative disorders) – frequency unknown.

 

Psychiatric disorders: Mood altered.

 

Vascular disorder: Vasculitis, hypotension, thromboembolic events (e.g. thrombophlebitis, pulmonary embolism, arterial, cerebral, deep vein or retinal vein thrombosis).

 

General disorders and administration site conditions: Oedema, injection site reaction*, injection site necrosis* (frequency not known).

*(parenteral only).

 

Adverse reactions following intrathecal methotrexate are generally classified into three groups, acute, subacute, and chronic. The acute form is a chemical arachnoiditis manifested by headache, back or shoulder pain, nuchal rigidity, and fever. The subacute form may include paresis, usually transient, paraplegia, nerve palsies, and cerebellar dysfunction. The chronic form is a leukoencephalopathy manifested by irritability, confusion, ataxia, spasticity, occasionally convulsions, dementia, somnolence, coma, and rarely, death. There is evidence that the combined use of cranial radiation and intrathecal methotrexate increases the incidence of leukoencephalopathy.

 

Additional reactions related to or attributed to the use of methotrexate such as osteoporosis, abnormal (usually 'megaloblastic') red cell morphology, precipitation of diabetes, other metabolic changes, and sudden death have been reported.

 

Post-marketing adverse drug reaction: Non-melanoma skin cancer as a very rare adverse drug event.

 

Reporting of suspected adverse reactions:

Reporting suspected adverse reactions after marketing authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions according to their local country requirements.

 

To Report side effects

 

·       Saudi Arabia

 

National Pharmacovigilance Centre (NPC)

·       Call center: 19999

·       E-mail: npc.drug@sfda.gov.sa

·       Website: https://ade.sfda.gov.sa/

 

·       Other GCC states

 

-        Please Contact the relevant competent authority.


Cases of overdose have been reported, sometimes fatal, due to erroneous daily intake instead of weekly intake of oral methotrexate In these cases, symptoms that have been commonly reported are hematological and gastrointestinal reactions.

 

Calcium folinate (calcium leucovorin) is a potent agent for neutralizing the immediate toxic effects of methotrexate on the haematopoietic system. Where large doses or overdoses are given, calcium folinate may be administered by intravenous infusion in doses up to 75 mg within 12 hours, followed by 12 mg intramuscularly every 6 hours for 4 doses. Where average doses of methotrexate appear to have an adverse effect 6-12 mg of calcium folinate may be given intramuscularly every 6 hours for 4 doses. In general, where overdosage is suspected, the dose of calcium folinate should be equal to or higher than, the offending dose of methotrexate and should be administered as soon as possible; preferably within the first hour and certainly within 4 hours after which it may not be effective.

 

Other supporting therapy such as blood transfusion and renal dialysis may be required.  Effective clearance of methotrexate has been reported with acute, intermittent haemodialysis using a high flux dialyser. 

 


Methotrexate is an antimetabolite which acts principally by competitively inhibiting the enzyme, dihydrofolate reductase. In the process of DNA synthesis and cellular replication, folic acid must be reduced to tetrahydrofolic acid by this enzyme, and inhibition by methotrexate interferes with tissue cell reproduction. Actively proliferating tissues such as malignant cells are generally more sensitive to this effect of methotrexate. It also inhibits antibody synthesis.

 

Methotrexate also has immunosuppressive activity, in part possibly as a result of inhibition of lymphocyte multiplication. The mechanism(s) of action in the management of rheumatoid arthritis of the drug is not known, although suggested mechanisms have included immunosuppressive and/or anti-inflammatory effect.


In doses of 0.1 mg (of methotrexate) per kg, methotrexate is completely absorbed from the gastrointestinal tract; larger oral doses may be incompletely absorbed. Peak serum concentrations are achieved within 0.5 - 2 hours following intravenous, intramuscular or intraarterial administration. Serum concentrations following oral administration of methotrexate may be slightly lower than those following intravenous injection.

 

Methotrexate is actively transported across cell membranes. The drug is widely distributed into body tissues with highest concentrations in the kidneys, gall bladder, spleen, liver and skin. Methotrexate is retained for several weeks in the kidneys and for months in the liver. Sustained serum concentrations and tissue accumulation may result from repeated daily doses. Methotrexate crosses the placental barrier and is distributed into breast milk. Approximately 50% of the drug in the blood is bound to serum proteins.

 

In one study, methotrexate had a serum half-life of 2-4 hours following intramuscular administration. Following oral doses of 0.06 mg/kg or more, the drug had a serum half-life of 2-4 hours, but the serum half-life was reported to be increased to 8-10 hours when oral doses of 0.037 mg/kg were given.

 

Methotrexate does not appear to be appreciably metabolised. The drug is excreted primarily by the kidneys via glomerular filtration and active transport. Small amounts are excreted in the faeces, probably via the bile. Methotrexate has a biphasic excretion pattern. If methotrexate excretion is impaired accumulation will occur more rapidly in patients with impaired renal function. In addition, simultaneous administration of other weak organic acids such as salicylates may suppress methotrexate clearance.

 


Not applicable

 


Sodium chloride, sodium hydroxide and water for injections


Immediate precipitation or turbidity results when combined with certain concentrations of droperidol, heparin sodium, metoclopramide hydrochloride, ranitidine hydrochloride in syringe.


As packaged for sale – 2 years After dilution – chemical and physical in-use stability has been demonstrated in dextrose 5% and sodium chloride 0.9% infusion solutions for 30 days at 4°C in PVC containers when protected from light. From a microbiological point of view the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions. Do not use Methotrexate after the expiry date which is stated on the Vial label after EXP:. The expiry date refers to the last day of that month.

As packaged for sale –

For the 50 mg/2 ml and 500 mg/20 ml presentations: Do not store above 25°C. Do not freeze. Keep container in the outer carton.

 

After dilution – see section 6.3.


50 mg/2 ml - Conventional or Onco-Tain Type I glass vial with rubber stopper, aluminium seal and plastic ‘flip-off’ top. Packs containing 5 vials.

 

500 mg/20ml - Conventional, or Onco-Tain Type I glass vial with rubber stopper, aluminium seal and plastic ‘flip-off’ top. Packs containing 1 vial.


Keep out of the sight and reach of children.

 

Single use only. Discard any unused contents.

 

Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

 


Hospira UK Limited Horizon Honey Lane Hurley Maidenhead SL6 6RJ UK

October 2023
}

صورة المنتج على الرف

الصورة الاساسية